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1. Elevated pulse pressure and cardiovascular risk associated in Spanish population attended in primary care: IBERICAN study

Author

Ana Moyá-Amengual, Antonio Ruiz-García, Vicente Pallarés-Carratalá, Adalberto Serrano-Cumplido, Miguel Ángel Prieto-Díaz, Antonio Segura-Fragoso, Sergio Cinza-Sanjurjo, the researchers of the IBERICAN study, Alfonso Barquilla García, Ángel Díaz Rodríguez, Carlos Escobar Cervantes, Francisco Javier Alonso Moreno, Jesús Vergara Martín, Juan José Badimón, José Polo García, Luis Rodríguez Padial, Miguel Ángel Prieto, Rafael Vidal Pérez, Sergio Cinza Sanjurjo, Sònia Miravet Jiménez, Sonsoles Velilla Zancada, José Ramón Banegas, Vicente Martín Sánchez, Vicente Pallares Carratalá, Antonio Segura Fragoso y Rafael Manuel Micó Pérez, Antonio López Téllez, Jesús Vergara Martin, María De Los Ángeles Ortega Osuna, Cristóbal Prieto Cid, Mª José Hidalgo Fajardo, José Lorente Serna, Ángel Domínguez Requena, Ricardo Alberola Cañizares, Manuel Ruiz Peña, Filomena Herrero Collado, Marcela Montes Vázquez, Rafael Ángel Carrascal Garrido, María Reyes Herrera Lozano, Beatriz Ortiz Oliva, Francisco José Anguita, Carmen Pérez Ibáñez, Carlos Alberto Cabrera Rodríguez, María José Cruz Rodríguez, Sandra Bonilla Ruiz, Rocio Reina González, Salome Abad Sánchez, Inmaculada Santana Martínez, Rafael Sánchez Jordán, Juan Mª Ramos Navas-Parejo, José Manuel Ramírez Torres, José María Beltrán Poveda, María Adoración De Cruz Benayas, Carmen Fernández Gil, Jon Iñaki Esturo Alcaine, Antonio Mora Quintero, Fernando Leiva Cepas, José Luis Carrasco Martín, Emilio García Criado, Mercedes Vázquez Blanco, Isabel Mora Ortiz, Leovigildo Ginel Mendoza, Juan Carlos Aguirre Rodríguez, Esperanza María Romero Rodríguez, José Acevedo Vázquez, Juan Gabriel García Ballesteros, María De La Paz Fernández Lara, Patricia Agüera Moreno, Eduardo Paños Maturana, Juan Manuel Ignacio Expósito, Noelia Carrillo Peñas, Carmen María Abad Faya, Ana Marina Almagro Duque, Rubén Torrescusa Camisón, Paloma Menéndez Polo, Marina Peña García, Cristina López Fernández, Ascensión Estepa Torres, Miguel Gutiérrez Jansen, Esperanza Loizaga González, Lisardo García Matarín, Enrique José Gamero De Luna, Javier Benítez Rivero, María José Gómez González, Carmen Gómez Montes, Juan Carlos Rodríguez Rodríguez, Juana María González Barranco, Josefa Ramírez Vizcaíno, María Ángeles Miranda Sánchez, Eva Trillo Calvo, Concepción Bayod Calvo, Susana Larripa De La Natividad, German Grasa Lambea, Emilio Jiménez Marín, Ana Cristina Navarro Gonzalvo, Antonio Pablo Martínez Barseló, Irene Peña León, Ángel González Pérez, Liliana Mahulea, María José Pérez Martínez, Ana Piera Carbonell, Margarita Alonso Fernández, María Montserrat Rueda Cuadrado, Rodrigo Abad Rodríguez, José Miguel Álvarez Cabo, Rubén Sánchez Rodríguez, Eva María Cano Cabo, Anny Romero Secin, Miguel Ángel Prieto Díaz, Juan Jesús García Fernández, Saúl Suárez García, Fernando García Romanos, Antonia Moreno González, María Lara Amengual Sastre, Susana Martínez Palli, José Alfonso Ramón Bauza, Jose Ortiz Bolinches, Carmen Fernández Fernández, María Isabel Orlandis Vázquez, Ana Sanchís Mezquita, Fernando Unceta Aramburu, Juan Fernando Peiró Morant, Ana Moyá Amengual, Matéu Seguí-Díaz, José Félix Zuazagoitia Nubla, Ana Echevarría Ituiño, Gregorio Mediavilla Tris, María Carmen Noriega Bosch, Esther González, María Luisa Ruiz Macho, Ruth Sendino Del Olmo, Asunción Olagorta De Prado, Ana López De Viñaspre Muguerza, Jesús Iturralde Iriso, Mª Rosario Virtus Iñurrieta, Lucas Ulloa Bahamonde, Isidro Godoy García, Fernando Rubio Sevillano, María Isabel González González, Marta Pérez Souto, Raquel De León Contreras, Sara Isabel Almeida González, Irene Almería Diez, Virginia Maria Mirabal Sánchez, Francisco José Escobar Lavado, Yoel Anta Pérez, Nayra Sánchez Hernández, Juan Luis Alonso Jerez, Ricardo Koch, Nayra Ramírez Mendoza, Héctor Suárez Hernández, Francisco Jesús Morales Escobar, E Lidia Gutiérrez Fernández, Fernando Andrés Mantecón, Ana Belén García Garrido, Asunción Vélez Escalante, Luisa Alonso Rentería, Jesús Sainz Jiménez, Guillermo Pombo Alles, Esperanza Rueda Alonso, Juan Antonio Divisón Garrote, Pedro Martínez Sotodosos, Juan Antonio Vivancos Fuster, María García Palencia, José Ambrosio Torres Moraleda, Sara González Ballesteros, Ana Carmen Gil Adrados, Antonio González Cabrera, Miguel Ángel Babiano Fernández, Guillermo Rico García, Juan José Criado-Álvarez, Pilar Torres Moreno, Francisco Javier Arribas Aguirregaviria, Alicia Sahuquillo Martínez, Lourdes Maria Santos Bejar, Miguel Laborda Peralta, Raúl Piedra Castro, Carlos Santos Altozano, Lucia González-Tarrio Polo, Pedro Valiente Maresca, Reinilda Mota Santana, Noemi Elizabeth Terrero Ledesma, Noelia Garrido Espada, Gabriela Delia Rosa Zambrana Calvi, Cristina de Castro Mesa, Blanca Cordero García, Pilar Sorrius Sitges, Ana María de Santiago Nocito, César Lozano Suárez, Juan Lorenzo Gutiérrez Montero, Juan Ignacio López Gil, María Dolores Fernández Ortega, Miren Elizari Roncal, María Ascensión López Serrano, Nuria Esther Adrián De La Fuente, Belén Angulo Fdez. De Larrea, Naiara Cubelos Fernández, Guiomar Luz Ferreiro Gómez, Diana Gómez Rodríguez, Sonia María Andrés Tuñón, María Ajenjo González, Serafín De Abajo Olea, Juan José León Regueras, César Manuel Gallego Nieto, Delio Vázquez Mallada, Maria De La O Gutiérrez García, Pablo Baz Rodríguez, José Ignacio Ferradal García, Blanca Delia De Román Martínez, Ana Arconada Pérez, Omar Mahmoud Atoui, Álvaro Morán Bayón, María Teresa Armenteros Del Olmo, Francisco Javier García-Norro Herreros, Enrique Méndez Rodríguez, Diana María Narganes Pineda, Verónica Ortiz Ainaga, Milagros Sonlei Sánchez Guevara, Laura Villota Ferreiro, M Teresa Grande Grande, Francisco Vicente Martínez Gracia, Jesús Palomo del Arco, María Dolores Moriano García, Beatriz Jiménez Muñoz, Gemma Rovira Marcelino, Diana Elizabeth Fernández Valverde, Roser Rodó Bernadó, Maria Teresa Ortiz Lupiañez, Najlaa Najih, José María Diéguez Parra, Mª Rosa Benedicto Acebo, Mari Luz Bravo Vicien, Alberto Ramón León Estella, Juan Antonio Muñoz Gómez, Alicia Mostazo Muntané, Isabel Ortega Abarca, Anna Gasol Fargas, Brenda Elizabeth Riesgo Escudero, Susana Elizabeth Riesgo, Edgar Zaballos Castellvi, Celia Cols Sagarra, Marta Herranz Fernández, Josep Alins Presas, Idaira Damas Pérez, Rosa M Alcolea Garcia, Ines Monte Collado, Roberto Genique Martínez, María José Guasch Villanueva, Teresa Rama Martínez, Lucio Pinto Pena, Josefa María Panisello Royo, Inés Gil Gil, Carlos Gómez Ruiz, Rita Sahun Font, Anna Fuentes Lloveras, Alberto Calderón Montero, María Del Mar Zamora Gómez, Elena Alarcón Cebrián, Mª José Piñero Acin, Celia Pecharroman Sacristán, M Soledad Mayayo Vicente, Mª Paz Pérez Unanua, Nuria Marañón Henrich, Saray Gómez Monreal, Sonia Redondo De Pedro, Blanca Sanz Pozo, Irene Moreno Martínez, Beatriz Lopez Uriarte, Carmelina Sanz Velasco, Amaya Gárriz Aguirre, Montserrat Rivera Teijido, German Reviriego Jaén, Jose Ignacio Aza Pascual-Salcedo, Josefa Vázquez Gallego, Julia Caballer Rodilla, Aida Herrera, Ezequiel Arranz Martínez, Ana María Gómez Calvo, Paula Morán Oliva, Mª Milagros González Béjar, Julio Antonio Heras Hitos, Olga García Vallejo, Manuel De Jesús Frías Vargas, María Jesús Castillejo Boguerin, Aurora García Lerín, Miguel Ángel María Tablado, Elena Concepción García García, Leticia De Miguel Acero, Carmen Zárate Oñate, Aránzazu Barranco Apoita, María Ester Montes Belloso, Ana María Huertas Velasco, Rafael Sáez Jiménez, Julia Natividad García Pascual, María Clemencia Zuluaga Zuluaga, Mª Cruz Díez Pérez, Antonio Ruiz García, Cristina Murillo Jelsbak, Virginia Lasso Oria, Amelia González Gamarra, Elena Rodilla Rodilla, Alberto Galgo Nafría, María Mestre de Juan, Mª Carmen García Albiñana, Mª del Pilar Moreno Cano, Paula Hernanz López, Paloma Casado Pérez, Jacinto Espinosa García, José Ignacio Prieto Romo, Leandro Fernández Fernández, Javier Sierratapia, Nieves Moreno Regidor, Francisco Javier Zaballos Sánchez, Ana Moreno Moreno, Francisco Carramiñana Barrera, Juan Jose Torres Vázquez, María José Gamero Samino, Miguel Ángel De Santiago Rodríguez, Pablo Rafael Gómez Martínez, Antonio Carlos Elías Becerra, Javier Soto Olivera, Víctor Cambero, Julián Domínguez Ávila, Andrés Simón Fuentes, Jorge Manuel De Nicolás Jiménez, Dimas Igual Fraile, Guadalupe Nieto Barco, Ignacio Araujo Ramos, Mª Luz Serrano Berrocal, Francisco Buitrago Ramírez, Minerva Gallego Marcos, Félix Suarez González, Victoriano Chavero Carrasco, Francisco Guerra Peguero, Francisco Javier Sánchez Vega, Manuel Tejero Mas, Alba Palmerín Donoso, Miguel Turégano Yedro, María Beatriz Esteban Rojas, Fátima Cabezudo Moreno, Nawson Elver Quevedo Saldaña, María Del Mar García Fenés, Timotea Garrote Florencio, José María Fernández Toro, Vicente Caballero Pajares, María José Gómez Barquero, Alejandra Rey Rañal, Elena García Del Río, Enrique Nieto Pol, Julio Álvarez Fernández, Pilar Alonso Álvarez, Mª Luisa Jorge Gómez, Antonio Calvo Guerrero, Isabel Celemín Colomina, Lucia Barreiro Casal, Juana Fernández Moreno, Mª Angelines Carballal Martínez, Nabor Díaz Rodríguez, Carlos Moral Paredes, Dolores Recarey García, Francisco Javier Iglesias Mato, Antonio Fouz Ulloa, Amparo Fidalgo González, Noelia Dios Parada, Patricia Conde Sabarís, Ana Isabel Rodríguez Pérez, Ana Inés García Palacio, Víctor Julio Quesada Varela, Lidia Romero Iglesias, Ángel Lado Llerena, Carmen Lires Rodríguez, María Luisa Carretero Díaz, José Carreira Arias, José Luís Vázquez Camino, María Del Carmen Torreiro Penas, Sandra Yáñez Freire, Daniel Rey Aldana, Carlos Piñeiro Díaz, Portal González Lorenzo, José Rodríguez Campos, Rubén Blanco Rodríguez, Manuel Portela Romero, Lucía Vilela de Castro, Sonsoles María Velilla Zancada, Rafael Crespo Sabarís, Oscar Fernando Isaula Jiménez, Jesús Manuel González Puga, Jorge Antonio Benaín Ávila, Óscar Del Toro González, Vicente Llorca Bueno, Ana María Ballesteros Pérez, Domingo J Rubira López, Mª Dolores Esteve Franco, Elena Sánchez Pablo, María Teresa Palacios López, Juan Castillo Meroño, José María Lobo Martínez, Isabel María Peral Martínez, J Eduardo Carrasco Carrasco, Armando Santo González, Juan Gomáriz García, Beatriz Ríos Morata, Laura Sánchez Iñigo, Inés Sanz Pérez, Vicente Pascual Fuster, Mª Dolores Aicart Bort, Natividad Vázquez Gómez, Carlos Lluna Gasco, Teresa Amorós Barber, Pedro Antonio Medina Cano, Miguel Monteagudo Moncho, María Jesús Larré Muñoz, Raquel Navarro Hernández, Francisco José Martínez Egea, Antonio Tramontano, Marta Ferrer Royo, Belén Persiva Saura, Juan A Contreras Torres, José Mª Tirado Moliner, Alejandro Salanova Penalba, Ariadna Cucó Alberola, Fernando María Navarro I Ros, Enrique Beltrán Llicer, Ana Seoane Novás, Inmaculada Martín Valls, Gracia Verdú Mahiques, Enrique Peña Forcada, Nieves Aguilar Gómez, Francisco Javier Sanz García, María Dolores Paradís Bueso, María Eugenia Alegre Romero, Antonio Francés Camus, María Amparo Antón Peinado, Rosa Latorre Santos, Mª Asunción Palomar Marín, María Carmen Botella García, Eva Sánchez Fresquet, Pedro Sala Paños, Tomás Sánchez Ruiz, Rosa Ana Valero Valero, María Seoane Vicente, Magdalena Martin Llinares, Antonio Masiá Alegre, José Luis Llisterri Caro, Irene Lluch Verdu, Vicente Pallarés Carratalá, Francisco Valls Roca, Rafael Manuel Micó Pérez, Carmen Barceló Dupuy, Elena Benages Vicente, María José Gimeno Tortajada, Mercedes Calleja del Ser, Martín Menéndez Rodríguez, and Rosalía Victoria Carbonell Castelló

Subjects
hypertension, pulse pressure, cardiovascular risk factors, subclinical target organ damage, hypertensive cardiovascular disease, cardiovascular disease, Diseases of the circulatory (Cardiovascular) system, RC666-701
Abstract

IntroductionElevated pulse pressure (ePP) is an independent marker of cardiovascular risk (CVR) in people older than 60, and a functional marker of subclinical target organ damage (sTOD) which can predict cardiovascular events in patients with hypertension (HTN), regardless of sTOD.ObjectiveTo evaluate the prevalence of ePP in adult population seen in primary care and its association with other vascular risk factors, sTOD and with cardiovascular disease (CVD).Materials and methodsObservational multicentre study conducted in Spain (8,066 patients, 54.5% women) from the prospective cohort study IBERICAN recruited in Primary Care. Pulse pressure (PP) was defined as the difference between the systolic blood pressure (SBP) and the diastolic blood pressure (DBP) ≥60 mmHg. Adjusted (for age and sex) ePP prevalence were determined. Bivariate and multivariate analyses of the possible variables associated with ePP were carried out.ResultsThe mean of PP was 52.35 mmHg, and was significantly higher (p

Published
2023
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2. Circulating tumor DNA for comprehensive noninvasive monitoring of lymphoma treated with ibrutinib plus nivolumab

Author

Michael Schaffer, Valeria Spina, Maria Cristina Pirosa, Ricardo Koch, Sriram Balasubramanian, Bernhard Gerber, Gabriela Forestieri, Alessio Bruscaggin, Brendan P. Hodkinson, Lodovico Terzi di Bergamo, M. Faderl, Nele Fourneau, John Alvarez, Wei Wu, Georg Stussi, Ferdinando Bonfiglio, Davide Rossi, Adalgisa Condoluci, and Emanuele Zucca

Subjects
Oncology, medicine.medical_specialty, Somatic evolution in cancer, Deep sequencing, Circulating Tumor DNA, chemistry.chemical_compound, Piperidines, Internal medicine, medicine, Humans, Bruton's tyrosine kinase, Lymphoid Neoplasia, biology, business.industry, Adenine, Cancer, Hematology, medicine.disease, Lymphoma, Clinical trial, Nivolumab, Pyrimidines, chemistry, Ibrutinib, biology.protein, Lymphoma, Large B-Cell, Diffuse, business
Abstract

Key Points ctDNA technology is useful for noninvasive monitoring of lymphoma treated with targeted agents in the clinical trial setting.An early >2-log reduction of ctDNA levels after 2 treatment cycles was a confirmed threshold for molecular response., Visual Abstract, To advance the use of circulating tumor DNA (ctDNA) applications, their broad clinical validity must be tested in different treatment settings, including targeted therapies. Using the prespecified longitudinal systematic collection of plasma samples in the phase 1/2a LYM1002 trial (registered on www.clinicaltrials.gov as NCT02329847), we tested the clinical validity of ctDNA for baseline mutation profiling, residual tumor load quantification, and acquisition of resistance mutations in patients with lymphoma treated with ibrutinib+nivolumab. Inclusion criterion for this ancillary biological study was the availability of blood collected at baseline and cycle 3, day 1. Overall, 172 ctDNA samples from 67 patients were analyzed by the LyV4.0 ctDNA Cancer Personalized Profiling Deep Sequencing Assay. Among baseline variants in ctDNA, only TP53 mutations (detected in 25.4% of patients) were associated with shorter progression-free survival; clones harboring baseline TP53 mutations did not disappear during treatment. Molecular response, defined as a >2-log reduction in ctDNA levels after 2 cycles of therapy (28 days), was achieved in 28.6% of patients with relapsed diffuse large B-cell lymphoma who had ≥1 baseline variant and was associated with best response and improved progression-free survival. Clonal evolution occurred frequently during treatment, and 10.3% new mutations were identified after 2 treatment cycles in nonresponders. PLCG2 was the topmost among genes that acquired new mutations. No patients acquired the C481S BTK mutation implicated in resistance to ibrutinib in CLL. Collectively, our results provide the proof of concept that ctDNA is useful for noninvasive monitoring of lymphoma treated with targeted agents in the clinical trial setting.

Published
2021
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3. Gestão de Resíduos Sólidos de uma Empresa de Aglomerados - um Olhar para Sustentabilidade

Author

Marciano Ricardo Koch, Odorico Konrad, Eduardo Miranda Ethur, Ana Christina Konrad, Marluce Lumi, and Lorenzo Zorzi

Subjects
gestão de resíduos, resíduos de madeira, sustentabilidade., Environmental sciences, GE1-350
Abstract

O objetivo principal deste trabalho é identificar quais tipos de resíduos sólidos provenientes das indústrias moveleiras podem ser potencializados para reaproveitamento na fabricação de novas chapas de aglomerado e/ou para geração de energia. Para tanto, foram identificadas as principais indústrias de móveis que utilizam como matéria prima o MDP e MDF junto ao SINDMÓVEIS de Bento Gonçalves. O método utilizado foi de pesquisa aplicada quanto aos fins e pesquisa documental, bibliográfica e estudo de caso quanto aos meios. O trabalho buscou quantificar e evidenciar o aproveitamento destes resíduos como matérias-primas alternativas tanto na produção de novas chapas de aglomerado como para geração de energia (biomassa). Os resultados obtidos mostram que há grande quantidade de resíduos gerados no polo moveleiro de Bento Gonçalves, onde, comparando-os com a quantidade de resíduos de matérias-primas virgens utilizadas na empresa de aglomerados, o aproveitamento destes resíduos alternativos reduziria consideravelmente o consumo de florestas plantadas.

Published
2014

4. Prevalencia de la enfermedad renal crónica y factores asociados en la población asistida en atención primaria de España: resultados del estudio IBERICAN

Author

José Luis Llisterri, Rafael Manuel Micó-Pérez, Sonsoles Velilla-Zancada, Gustavo Cristóbal Rodríguez-Roca, Miguel Ángel Prieto-Díaz, Vicente Martín-Sánchez, Alfonso Barquilla, José Polo-García, Antonio Segura-Fragoso, Sergio Cinza-Sanjurjo, Alfonso Barquilla García, Ángel Díaz Rodríguez, Carlos Escobar Cervantes, Francisco Javier Alonso Moreno, Gustavo Cristóbal Rodríguez Roca, Jesús Vergara Martín, José Luis Llisterri Caro, Juan José Badimón, José Polo García, Luis Rodríguez Padial, Miguel Ángel Prieto, Rafael Vidal Pérez, Sergio Cinza Sanjurjo, Sonia Miravet Jiménez, Sonsoles Velilla Zancada, Antonio López Téllez, Maria de Los Ángeles Ortega Osuna, Cristóbal Prieto Cid, María José Hidalgo Fajardo, José Lorente Serna, Ángel Domínguez Requena, Ricardo Alberola Cañizares, Manuel Ruiz Peña, Filomena Herrero Collado, Marcela Montes Vázquez, Rafael Ángel Carrascal Garrido, María Reyes Herrera Lozano, Beatriz Ortiz Oliva, Francisco José Anguita, Carmen Pérez Ibáñez, Carlos Alberto Cabrera Rodríguez, María José Cruz Rodríguez, Sandra Bonilla Ruiz, Rocío Reina González, Salomé Abad Sánchez, Inmaculada Santana Martínez, Rafael Sánchez Jordán, Juan María Ramos Navas-Parejo, José Manuel Ramírez Torres, José María Beltrán Poveda, María Adoración de Cruz Benayas, Carmen Fernandez Gil, Jon Iñaki Esturo Alcaine, Antonio Mora Quintero, Fernando Leiva Cepas, José Luis Carrasco Martín, Emilio García Criado, Mercedes Vázquez Blanco, Isabel Mora Ortiz, Leovigildo Ginel Mendoza, Juan Carlos Aguirre Rodríguez, Esperanza María Romero Rodríguez, José Acevedo Vázquez, Juan Gabriel García Ballesteros, María de La Paz Fernández Lara, Patricia Agüera Moreno, Eduardo Paños Maturana, Juan Manuel Ignacio Expósito, Noelia Carrillo Peñas, Carmen María Abad Faya, Ana Marina Almagro Duque, Rubén Torrescusa Camisón, Paloma Menéndez Polo, Marina Peña García, Cristina López Fernández, Ascensión Estepa Torres, Miguel Gutiérrez Jansen, Esperanza Loizaga González, Lisardo García Matarin, Enrique José Gamero de Luna, Javier Benítez Rivero, María José Gómez González, Carmen Gómez Montes, Eva Trillo Calvo, Concepción Bayod Calvo, Susana Larripa de La Natividad, Germán Grasa Lambea, Emilio Jiménez Marín, Ana Cristina Navarro Gonzalvo, Antonio Pablo Martínez Barseló, Irene Peña León, E. Lidia Gutiérrez Fernández, Fernando Andrés Mantecón, Ana Belén García Garrido, Asunción Velez Escalante, Luisa Alonso Rentería, Jesús Sainz Jiménez, Guillermo Pombo Alles, Juan Antonio Divison Garrote, Pedro Martínez Sotodosos, Juan Antonio Vivancos Fuster, María García Palencia, José Ambrosio Torres Moraleda, Sara González Ballesteros, Ana Carmen Gil Adrados, Antonio González Cabrera, Miguel Ángel Babiano Fernández, Guillermo Rico García, Juan José Criado-Álvarez, Pilar Torres Moreno, Francisco Javier Arribas Aguirregaviria, Alicia Sahuquillo Martínez, Lourdes María Santos Béjar, Miguel Laborda Peralta, Raúl Piedra Castro, Carlos Santos Altozano, Lucía González-Tarrio Polo, Pedro Valiente Maresca, Reinilda Mota Santana, Noemi Elizabeth Terrero Ledesma, Noelia Garrido Espada, Gabriela Delia Rosa Zambrana Calvi, Juan Lorenzo Gutiérrez Montero, Juan Ignacio López Gil, María Dolores Fernández Ortega, Miren Elizari Roncal, María Ascensión López Serrano, Nuria Esther Adrián de La Fuente, Belén Angulo Fdez. de Larrea, Naiara Cubelos Fernández, Guiomar Luz Ferreiro Gómez, Diana Gómez Rodríguez, Sonia María Andrés Tuñón, María Ajenjo González, Serafín de Abajo Olea, Juan José León Regueras, César Manuel Gallego Nieto, Delio Vázquez Mallada, Maria de La O Gutiérrez García, Pablo Baz Rodríguez, José Ignacio Ferradal García, Blanca Delia de Román Martínez, Ana Arconada Pérez, Omar Mahmoud Atoui, Álvaro Morán Bayón, María Teresa Armenteros del Olmo, Fco. Javier García-Norro Herreros, Enrique Méndez Rodríguez, Diana María Narganes Pineda, Verónica Ortiz Ainaga, Milagros Sonlei Sánchez Guevara, Laura Villota Ferreiro, M. Teresa Grande Grande, Francisco Vicente Martínez Gracía, María Dolores Moriano García, Beatriz Jiménez Muñoz, Gemma Rovira Marcelino, Diana Elizabeth Fernández Valverde, Roser Rodó Bernadó, María Teresa Ortiz Lupiáñez, Najlaa Najih, José María Diéguez Parra, María Rosa Benedicto Acebo, Mari Luz Bravo Vicien, Alberto Ramón León Estella, Juan Antonio Muñoz Gómez, Alicia Mostazo Muntané, Isabel Ortega Abarca, Anna Gasol Fargas, Brenda Elizabeth Riesgo Escudero, Susana Elizabeth Riesgo, Edgar Zaballos Castellvi, Celia Cols Sagarra, Marta Herranz Fernández, Josep Alins Presas, Idaira Damas Pérez, Rosa M. Alcolea García, Inés Monte Collado, Roberto Genique Martínez, María José Guasch Villanueva, Teresa Rama Martínez, Lucio Pinto Pena, Josefa María Panisello Royo, Inés Gil Gil, Alberto Calderón Montero, María del Mar Zamora Gómez, Elena Alarcón Cebrián, María José Piñero Acin, Celia Pecharromán Sacristán, M. Soledad Mayayo Vicente, María Paz Pérez Unanua, Nuria Marañón Henrich, Saray Gómez Monreal, Sonia Redondo de Pedro, Blanca Sanz Pozo, Irene Moreno Martínez, Beatriz López Uriarte, Carmelina Sanz Velasco, Amaya Gárriz Aguirre, Montserrat Rivera Teijido, Germán Reviriego Jaén, José Ignacio Aza Pascual-Salcedo, Josefa Vázquez Gallego, Julia Caballer Rodilla, Aida Herrera, Ezequiel Arranz Martínez, Ana María Gómez Calvo, Paula Morán Oliva, María Milagros González Béjar, Julio Antonio Heras Hitos, Olga García Vallejo, Manuel de Jesús Frías Vargas, María Jesús Castillejo Boguerin, Aurora García Lerin, Miguel Ángel María Tablado, Elena Concepción García García, Leticia de Miguel Acero, Carmen Zárate Oñate, Aránzazu Barranco Apoita, María Ester Montes Belloso, Ana María Huertas Velasco, Rafael Sáez Jiménez, Julia Natividad García Pascual, María Clemencia Zuluaga Zuluaga, María Cruz Díez Perez, Antonio Ruiz García, Cristina Murillo Jelsbak, Virginia Lasso Oria, Amelia González Gamarra, Vicente Pascual Fuster, María Dolores Aicart Bort, Natividad Vázquez Gómez, Carlos Lluna Gasco, Teresa Amoros Barber, Pedro Antonio Medina Cano, Miguel Monteagudo Moncho, María Jesús Larré Muñoz, Raquel Navarro Hernández, Francisco José Martínez Egea, Antonio Tramontano, Marta Ferrer Royo, Belén Persiva Saura, Juan A. Contreras Torres, José María Tirado Moliner, Alejandro Salanova Penalba, Ariadna Cucó Alberola, Fernando María Navarro I. Ros, Enrique Beltrán Llicer, Ana Seoane Novás, Inmaculada Martín Valls, Gracia Verdú Mahiques, Enrique Peña Forcada, Nieves Aguilar Gómez, Francisco Javier Sanz García, M. Dolores Paradís Bueso, María Eugenia Alegre Romero, Antonio Francés Camus, María Amparo Antón Peinado, Rosa Latorre Santos, María Asunción Palomar Marín, María Carmen Botella García, Eva Sánchez Fresquet, Pedro Sala Paños, Tomás Sánchez Ruiz, Rosa Ana Valero Valero, María Seoane Vicente, Magdalena Martín Llinares, Antonio Masiá Alegre, Irene Lluch Verdú, Vicente Pallares Carratala, Francisco Valls Roca, Rafael Manuel Micó Pérez, Jacinto Espinosa García, José Ignacio Prieto Romo, Leandro Fernández Fernández, Javier Sierratapia, Nieves Moreno Regidor, Francisco Javier Zaballos Sánchez, Ana Moreno Moreno, Francisco Carramiñana Barrera, Juan José Torres Vázquez, María José Gamero Samino, Miguel Ángel de Santiago Rodríguez, Pablo Rafael Gómez Martínez, Antonio Carlos Elías Becerra, Javier Soto Olivera, Víctor Cambero, Julián Domínguez Ávila, Andrés Simón Fuentes, Jorge Manuel de Nicolás Jiménez, Dimas Igual Fraile, Guadalupe Nieto Barco, Ignacio Araujo Ramos, María Luz Serrano Berrocal, Francisco Buitrago Ramírez, Minerva Gallego Marcos, Félix Suárez González, Victoriano Chavero Carrasco, Francisco Guerra Peguero, Francisco Javier Sánchez Vega, Manuel Tejero Mas, Alba Palmerín Donoso, Miguel Turégano Yedro, María Beatriz Esteban Rojas, Fátima Cabezudo Moreno, Nawson Elver Quevedo Saldaña, María del Mar García Fenés, Timotea Garrote Florencio, José María Fernández Toro, Alejandra Rey Rañal, Elena García del Río, Enrique Nieto Pol, Julio Álvarez Fernández, Pilar Alonso Álvarez, María Luisa Jorge Gómez, Antonio Calvo Guerrero, Isabel Celemín Colomina, Lucía Barreiro Casal, Juana Fernández Moreno, María Angelines Carballal Martínez, Nabor Díaz Rodríguez, Carlos Moral Paredes, Dolores Recarey García, Fco. Javier Iglesias Mato, Antonio Fouz Ulloa, Amparo Fidalgo González, Noelia Dios Parada, Patricia Conde Sabarís, Ana Isabel Rodríguez Pérez, Ana Inés García Palacio, Víctor Julio Quesada Varela, Lidia Romero Iglesias, Ángel Lado Llerena, Carmen Lires Rodríguez, María Luisa Carretero Diaz, José Carreira Arias, Jose Luis Vázquez Camino, María del Carmen Torreiro Penas, Sandra Yáñez Freire, Daniel Rey Aldana, Carlos Piñeiro Díaz, Fernando García Romanos, Antonia Moreno González, María Lara Amengual Sastre, Susana Martínez Palli, José Alfonso Ramón Bauza, José Ortiz Bolinches, Carmen Fernández Fernández, María Isabel Orlandis Vázquez, Ana Sanchís Mezquita, Fernando Unceta Aramburu, Juan Fernando Peiró Morant, Ana Moyá Amengual, Isidro Godoy García, Fernando Rubio Sevillano, María Isabel González González, Marta Pérez Souto, Raquel de León Contreras, Sara Isabel Almeida González, Irene Almería Diez, Virginia María Mirabal Sánchez, Francisco José Escobar Lavado, Yoel Anta Pérez, Nayra Sánchez Hernández, Juan Luis Alonso Jerez, Ricardo Koch, Nayra Ramírez Mendoza, Héctor Suárez Hernández, Francisco Jesús Morales Escobar, Sonsoles María Velilla Zancada, Rafael Crespo Sabarís, Óscar Fernando Isaula Jiménez, Jesús Manuel González Puga, Jorge Antonio Benaín Ávila, Óscar del Toro González, Laura Sánchez Íñigo, Inés Sanz Pérez, José Félix Zuazagoitia Nubla, Ana Echebarría Ituiño, Gregorio Mediavilla Tris, María Carmen Noriega Bosch, Esther González, María Luisa Ruiz Macho, Ruth Sendino del Olmo, Asunción Olagorta de Prado, Ana López de Viñaspre Muguerza, Jesús Iturralde Iriso, María José Pérez Martínez, Ana Piera Carbonell, Margarita Alonso Fernández, María Montserrat Rueda Cuadrado, Rodrigo Abad Rodríguez, José Miguel Álvarez Cabo, Rubén Sánchez Rodríguez, Eva María Cano Cabo, Anny Romero Secin, Miguel Ángel Prieto Díaz, Juan Jesús García Fernández, Vicente Llorca Bueno, Ana María Ballesteros Pérez, Domingo J. Rubira López, María Dolores Esteve Franco, Elena Sánchez Pablo, María Teresa Palacios López, Juan Castillo Meroño, José María Lobo Martínez, Isabel María Peral Martínez, J. Eduardo Carrasco Carrasco, and Armando Santo González

Subjects
Gynecology, 03 medical and health sciences, medicine.medical_specialty, 0302 clinical medicine, business.industry, medicine, 030212 general & internal medicine, General Medicine, business
Abstract

Resumen Objetivos Conocer la prevalencia de enfermedad renal cronica (ERC) y determinar los factores asociados al deterioro de la funcion renal en poblacion asistida en atencion primaria. Pacientes y metodo Estudio transversal y multicentrico realizado en los pacientes basales del estudio IBERICAN (identificacion de la poblacion espanola de riesgo cardiovascular y renal). Se considero ERC a un filtrado glomerular estimado (FGe) Resultados Se incluyeron 7.895 pacientes (edad media 57,9 ± 14,8 anos; 54,5% mujeres). El 14,4% (IC 95%: 13,6-15,1) presentaba ERC; en hombres un 16,1% (IC 95%: 14,9-17,3) y en mujeres un 12,9% (IC 95%: 11,9-14,0). Se observo un aumento continuo de la prevalencia con la edad (24,8% ≥ 65 anos) y con la agregacion de FRCV. Las variables que mas se asociaron a la probabilidad de padecer ERC fueron hipertrofia ventricular izquierda (OR: 1,95; p Conclusiones Catorce de cada 100 pacientes incluidos en el estudio IBERICAN presenta ERC. La prevalencia de ERC afecta a la cuarta parte de pacientes ≥ 65 anos y aumenta exponencialmente con la agregacion de FRCV.

Published
2021
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5. ADAPTATION OF CHRONIC LYMPHOCYTIC LEUKEMIA TO IBRUTINIB IS MEDIATED BY EPIGENETIC PLASTICITY OF RESIDUAL DISEASE AND BY‐PASS SIGNALING VIA MAPK PATHWAY

Author

D. Piffaretti, Franco Cavalli, V. Gattei, Tamara Bittolo, Michael Gregor, Jakob Passweg, Jui Wan Loh, Claudio Martines, Adalgisa Condoluci, Lorenzo De Paoli, Hossein Khiabanian, Antonella Zucchetto, Georg Stussi, Clara Deambrogi, Paolo Ghia, Lydia Scarfò, M. Faderl, Erika Tissino, L. Terzi di Bergamo, Bernhard Gerber, Emanuele Zucca, Amartya Singh, Ricardo Koch, Gianluca Gaidano, Francesco Autore, Davide Rossi, Francesco Passamonti, Silke Gillessen, Dimitar G. Efremov, Riccardo Moia, Silvia Rasi, Alessandra Tedeschi, K. Pini, Anna Maria Frustaci, Michele Merli, Wei Wu, Gabriela Forestieri, Valeria Spina, Marco Montillo, Luca Laurenti, and Alessio Bruscaggin

Subjects
MAPK/ERK pathway, Cancer Research, Chronic lymphocytic leukemia, Hematology, General Medicine, Disease, Biology, medicine.disease, chemistry.chemical_compound, Oncology, chemistry, Ibrutinib, medicine, Cancer research, Epigenetics, Adaptation
Published
2021
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6. IBRUTINIB TOLERABILITY AND OUTCOME IN PATIENTS WITH HIGH‐RISK CHRONIC LYMPHOCYTIC LEUKEMIA

Author

Francesco Autore, Alessio Bruscaggin, R. Mattarucchi, Alessandra Tedeschi, G. Fahrni, Anna Maria Frustaci, Ricardo Koch, M. Faderl, Georg Stussi, L. Terzi‐di‐Bergamo, Adalgisa Condoluci, Marina Deodato, Gabriela Forestieri, Paolo Ghia, Lydia Scarfò, Emanuele Zucca, D. Gussetti, Jakob Passweg, Valeria Spina, Silke Gillessen, Davide Rossi, Maria Cristina Pirosa, Riccardo Moia, V. Gattei, Luca Laurenti, D. Piffaretti, Michele Merli, Bernhard Gerber, Pietro Bulian, Franco Cavalli, K. Pini, Francesco Passamonti, Gianluca Gaidano, A. Zanatta, M. G. Cittone, Clara Deambrogi, and Michael Gregor

Subjects
Oncology, Cancer Research, medicine.medical_specialty, business.industry, Chronic lymphocytic leukemia, Hematology, General Medicine, medicine.disease, Outcome (game theory), chemistry.chemical_compound, Tolerability, chemistry, Internal medicine, Ibrutinib, medicine, In patient, business
Published
2021
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7. GENETIC AND PHENOTYPIC ATTRIBUTES OF SPLENIC MARGINAL ZONE LYMPHOMA

Author

D. Piffaretti, Manuela Mollejo, L. Terzi di Bergamo, M. G. Cittone, Liliana Devizzi, Guido Ghilardi, Estella Matutes, Elena Sabattini, Elisa Lucchini, Sílvia Beà, Lydia Scarfò, Sergio Cogliatti, Stefano Pileri, Davide Rossi, M. Án. Piris, Govind Bhagat, Gilles Salles, Armando López-Guillermo, Maria Joao Baptista, Emanuele Zucca, Alden A. Moccia, Alessandra Tucci, Vincenzo Canzonieri, M. Ladetto, Luca Arcaini, Renzo Boldorini, Gabriela Forestieri, Maria Cristina Pirosa, Elias Campo, Alessandro Broccoli, Thomas Tousseyn, Sascha Dietrich, Roberto Marasca, Gianluca Gaidano, Ricardo Koch, Enrico Derenzini, Fabio Facchetti, Juan F. García, Alexandar Tzankov, Michele Merli, Carlo Visco, Hossein Khiabanian, Francesca Guidetti, Franco Cavalli, Arianna Calcinotto, Francesco Passamonti, Thorsten Zenz, Giuseppe Gritti, Julia T. Geyer, Marco Lucioni, M. Ponzoni, M. Faderl, Francesco Bertoni, Anastasios Stathis, Antonino Maiorana, Urban Novak, L. de Leval, Alexandra Traverse-Glehen, Luca Mazzucchelli, Anna Guidetti, Gabriela Bastidas, Véronique Meignin, P. L. Zinzani, Luciano Cascione, Ferdinando Bonfiglio, Giorgio Inghirami, Felicitas Hitz, Stefano Pizzolitto, Alberto J. Arribas, Angela Rita Elia, Elisa Santambrogio, Georg Stussi, Catherine Thieblemont, David Oscier, Marco Paulli, Bernhard Gerber, Umberto Vitolo, Alessio Bruscaggin, Francesco Piazza, Stefan Dirnhofer, W. Wu, Paolo Ghia, Valeria Spina, L. Bonomini, K. Pini, Gustavo Tapia, M. G. Da Silva, Luca Ceriani, Carlos Montalbán, and Adalgisa Condoluci

Subjects
Cancer Research, Pathology, medicine.medical_specialty, Oncology, medicine, Hematology, General Medicine, Splenic marginal zone lymphoma, Biology, medicine.disease, Phenotype
Published
2021
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8. CIRCULATING TUMOR DNA IS A PROGNOSTIC BIOMARKER IN CLASSIC HODGKIN LYMPHOMA

Author

Bernhard Gerber, Jan Maciej Zaucha, A. Stasia, E. Borsatti, Carmelo Carlo-Stella, Alessio Bruscaggin, Valeria Spina, Salvatore Annunziata, Anastasios Stathis, M. Kurlapski, F. Cavalli, Alden A. Moccia, Luca Ceriani, Gabriela Forestieri, G. Romanowicz, D. Rossi, Antonello Pinto, Ricardo Koch, Gian Mauro Sacchetti, Gianluca Gaidano, Georg Stussi, Adalgisa Condoluci, Riccardo Moia, S. Chauvie, M. Faderl, Maria Cristina Pirosa, I. Zangrilli, S. Hohaus, K. Pini, S. Gillessen Sommer, M. G. Cittone, Pietro Bulian, M. di Trani, Emanuele Zucca, Marcello Rodari, D. Piffaretti, L. Terzi di Bergamo, and V. Gattei

Subjects
Cancer Research, Oncology, Circulating tumor DNA, business.industry, Cancer research, Hodgkin lymphoma, Medicine, Prognostic biomarker, Hematology, General Medicine, business
Published
2021
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9. Genetic and Phenotypic Attributes of Splenic Marginal Zone Lymphoma

Author

Alessio Bruscaggin, Francesco Passamonti, Thomas Tousseyn, Anna Guidetti, Luca Ceriani, Paolo Corradini, Francesco Piazza, Carlos Montalbán, Adalgisa Condoluci, Marco Bühler, Giorgio A. Vanini, Lodovico Terzi di Bergamo, M. Faderl, Urban Novak, Miguel A. Piris, Luisella Bonomini, Elena Sabattini, Liliana Devizzi, Govind Bhagat, Carlo Visco, Fabio Facchetti, Arianna Calcinotto, Francesca Guidetti, M. Ladetto, Umberto Vitolo, Francesco Bertoni, Armando López-Guillermo, Giuseppe Gritti, Thorsten Zenz, Valeria Spina, Renata Walewska, Marco Paulli, Julia T. Geyer, David Oscier, Catherine Thieblemont, Estella Matutes, Francesco Zaja, Elisa Lucchini, Alexandra Traverse-Glehen, Guido Ghilardi, Emanuele Zucca, Alberto J. Arribas, Renzo Boldorini, Marco Lucioni, Pier Luigi Zinzani, K. Pini, Alden A. Moccia, Stefano Pileri, Alexander Tzankov, Wu Wei, Angela Rita Elia, Maria Joao Baptista, Lydia Scarfò, Stefan Dirnhofer, Laurence de Leval, Sílvia Beà, Gabriela Bastidas, Alessandra Tucci, Giorgio Inghirami, Gianluca Gaidano, Gilles Salles, Felicitas Hitz, Enrico Derenzini, Gustavo Tapia, Ferdinando Bonfiglio, Alessandro Broccoli, Micol Giulia Cittone, Sascha Dietrich, Luca Arcaini, Paolo Ghia, Hossein Khiabanian, Michele Merli, Alessandro Rambaldi, Manuela Mollejo, Maria Cristina Pirosa, Deborah Piffaretti, Anastasios Stathis, Antonino Maiorana, Ricardo Koch, Juan F. García, Sergio Cogliatti, Gabriela Forestieri, Roberto Marasca, Stefano Pizzolitto, Elisa Santambrogio, Georg Stussi, Maurilio Ponzoni, Bernhard Gerber, Maria Gomes da Silva, Corrado Tarella, Luciano Cascione, Elias Campo, Luca Mazzucchelli, Davide Rossi, Véronique Meignin, Vincenzo Canzonieri, Franco Cavalli, Bonfiglio, Ferdinando, Bruscaggin, Alessio, Guidetti, Francesca, Terzi di Bergamo, Lodovico, Faderl, Martin Richard, Spina, Valeria, Condoluci, Adalgisa, Bonomini, Luisella, Forestieri, Gabriela, Koch, Ricardo, Piffaretti, Deborah, Pini, Katia, Pirosa, Maria C, Cittone, Micol Giulia, Arribas, Alberto, Lucioni, Marco, Ghilardi, Guido, Wu, Wei, Arcaini, Luca, Baptista, Maria Joao, Bastidas, Gabriela, Beà, Silvia, Boldorini, Renzo, Broccoli, Alessandro, Bühler, Marco Matteo, Canzonieri, Vincenzo, Cascione, Luciano, Ceriani, Luca, Cogliatti, Sergio B, Corradini, Paolo, Derenzini, Enrico, Devizzi, Liliana, Dietrich, Sascha, Elia, Angela Rita, Facchetti, Fabio, Gaidano, Gianluca, Garcia, Juan F, Gerber, Bernhard, Ghia, Paolo, Gomes da Silva, Maria, Gritti, Giuseppe, Guidetti, Anna, Hitz, Felicita, Inghirami, Giorgio Ga, Ladetto, Marco, López-Guillermo, Armando, Lucchini, Elisa, Maiorana, Antonino, Marasca, Roberto, Matutes, Estella, Meignin, Véronique, Merli, Michele, Moccia, Alden A, Mollejo, Manuela, Montalban, Carlo, Novak, Urban, Oscier, David Graham, Passamonti, Francesco, Piazza, Francesco A, Pizzolitto, Stefano, Rambaldi, Alessandro, Sabattini, Elena, Salles, Gilles Andre, Santambrogio, Elisa, Scarfo, Lydia, Stathis, Anastasio, Stussi, Georg, Geyer, Julia Turbiner, Tapia, Gustavo, Tarella, Corrado, Thieblemont, Catherine, Tousseyn, Thoma, Tucci, Alessandra, Vanini, Giorgio, Visco, Carlo, Vitolo, Umberto, Walewska, Renata, Zaja, Francesco, Zenz, Thorsten, Zinzani, Pier Luigi, Khiabanian, Hossein, Calcinotto, Arianna, Bertoni, Francesco, Bhagat, Govind, Campo, Elia, de Leval, Laurence, Dirnhofer, Stefan, Pileri, Stefano A, Piris, Miguel A, Traverse-Glehen, Alexandra, Tzankov, Alexander, Paulli, Marco, Ponzoni, Maurilio, Mazzucchelli, Luca, Cavalli, Franco, Zucca, Emanuele, and Rossi, Davide

Subjects
Genetically modified mouse, Male, Lymphoma, Immunology, Marginal Zone, 610 Medicine & health, Computational biology, Biology, Biochemistry, Immunophenotyping, Mice, medicine, Tumor Microenvironment, Aged, Animals, Chromosome Aberrations, Female, Humans, Lymphoma, B-Cell, Marginal Zone/diagnosis, Lymphoma, B-Cell, Marginal Zone/genetics, Middle Aged, Multigene Family, Mutation, Spleen/pathology, Splenic Neoplasms/diagnosis, Splenic Neoplasms/genetics, Transcriptome, SMZL. molecular oncology, Splenic marginal zone lymphoma, Gene, Mechanism (biology), Splenic Neoplasms, B-Cell, Cell Biology, Hematology, Lymphoma, B-Cell, Marginal Zone, medicine.disease, Phenotype, Primary tumor, Immune checkpoint, 610 Medizin und Gesundheit, Spleen
Abstract

Splenic marginal zone B-cell lymphoma (SMZL) is a heterogeneous clinico-biological entity. The clinical course is variable, multiple genes are mutated with no unifying mechanism, and essential regulatory pathways and surrounding microenvironments are diverse. We sought to clarify the heterogeneity of SMZL by resolving different subgroups and their underlying genomic abnormalities, pathway signatures, and microenvironment compositions to uncover biomarkers and therapeutic vulnerabilities. We studied 303 SMZL spleen samples collected through the IELSG46 multicenter international study (NCT02945319) by using a multiplatform approach. We carried out genetic and phenotypic analyses, defined self-organized signatures, validated the findings in independent primary tumor metadata and determined correlations with outcome data. We identified 2 prominent genetic clusters in SMZL, termed NNK (58% of cases, harboring NF-κB, NOTCH, and KLF2 modules) and DMT (32% of cases, with DNA-damage response, MAPK, and TLR modules). Genetic aberrations in multiple genes as well as cytogenetic and immunogenetic features distinguished NNK- from DMT-SMZLs. These genetic clusters not only have distinct underpinning biology, as judged by differences in gene-expression signatures, but also different outcomes, with inferior survival in NNK-SMZLs. Digital cytometry and in situ profiling segregated 2 basic types of SMZL immune microenvironments termed immune-suppressive SMZL (50% of cases, associated with inflammatory cells and immune checkpoint activation) and immune-silent SMZL (50% of cases, associated with an immune-excluded phenotype) with distinct mutational and clinical connotations. In summary, we propose a nosology of SMZL that can implement its classification and also aid in the development of rationally targeted treatments.

Published
2021
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10. CLL-358: Adaptation of Chronic Lymphocytic Leukemia to Ibrutinib Is Mediated by Epigenetic Plasticity of Residual Disease and Bypass Signaling via the MAPK Pathway

Author

Wei Wu, Dimitar G. Efremov, M. Faderl, Silke Gillessen, Deborah Piffaretti, Silvia Rasi, Georg Stussi, Lorenzo De Paoli, Michele Merli, K. Pini, Ricardo Koch, Francesco Passamonti, Hossein Khiabanian, Anna Maria Frustaci, Alessio Bruscaggin, Michael Gregor, Claudio Martines, Davide Rossi, Lydia Scarfò, Bernhard Gerber, Clara Deambrogi, Lodovico Terzi di Bergamo, Amartya Singh, Alessandra Tedeschi, Marco Montillo, Antonella Zucchetto, Gabriela Forestieri, Valeria Spina, Luca Laurenti, Franco Cavalli, Jakob Passweg, Adalgisa Condoluci, Riccardo Moia, Paolo Ghia, Jui Wan Loh, Gianluca Gaidano, Erika Tissino, Valter Gattei, Tamara Bittolo, Francesco Autore, and Emanuele Zucca

Subjects
MAPK/ERK pathway, Cancer Research, education.field_of_study, business.industry, Chronic lymphocytic leukemia, Population, breakpoint cluster region, Context (language use), Hematology, medicine.disease, Minimal residual disease, chemistry.chemical_compound, Oncology, chemistry, hemic and lymphatic diseases, Ibrutinib, Ulixertinib, medicine, Cancer research, education, business
Abstract

Context: Ibrutinib inhibits BTK with the most typical response in CLL being partial remission (PR) with measurable minimal residual disease (MRD) in blood. Remission is usually maintained until development of genetically-driven resistance. Objective: Mechanism of adaptation and survival in MRD. Patients and Methods: Pre-treatment CLL cells and under-treatment MRD were systematically collected from 33 high-risk CLL patients. Samples were characterized by high-dimensional, single-cell flow cytometry; bulk genomic, transcriptomic, and chromatin accessibility profiling; and single-cell RNA-seq profiling. Results: The genetic composition of MRD remained constant across timepoints, indicating that ibrutinib did not have any impact in shaping its genomic diversity. Ibrutinib induced chromatin dynamics in MRD resulting in a predominantly closed state. Chromatin regions that became more accessible under ibrutinib were enriched of binding sites for transcription factor that lay downstream ERK signaling. Regions that turned into a less accessible state were enriched for the binding sites of TF emanating from the BCR. At the transcriptomic level, most of the differentially expressed genes between pre- and post-treatment samples were downregulated in MRD, while only a fraction was upregulated. IL4, NF-kB, and metabolism and proliferation signatures were downregulated in MRD, while MAPK and RAS signatures were upregulated. CLL spleen samples from TCL1 mice under ibrutinib treatment showed an upregulation of MAPK pathway genes compared to untreated mice. Single-cell transcriptomes revealed a distinct post-treatment cell population driven by MAPK activity that functionally pre-existed in a fraction of CLL cells of baseline samples before ibrutinib start. At the signaling level, ibrutinib had no effect on the integrity of RAS-BRAF-MAPK-ERK pathway protein expression upon crosslinking of the BCR with anti-IgM but not after stimulation of TLR9 or CD40. Functional validation on primary samples by western blotting shows that RAS/ERK can be activated by BCR stimulation, irrespective of ibrutinib treatment in ex vivo experiments. Pharmacological inhibition of MEK (trametinib) and ERK (ulixertinib) synergized with ibrutinib, leading to decreased cell viability. Conclusions: MRD under ibrutinib adapts its phenotype in an epigenetic way to maintain functional competence of BCR signaling via the MAPK pathway, which turned to be a vulnerability of MRD persisting under ibrutinib.

Published
2021
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12. Evaluation of the Different Stratification Models for POD24 Prediction in Patients with Follicular Lymphoma

Author

Alexandra Valera, Davide Rossi, M. Faderl, K. Pini, Alessio Bruscaggin, Elena Flospergher, Michele Ghielmini, Bernhard Gerber, Lodovico Terzi-di-Bergamo, Riccardo Moia, Silke Gillessen, Stefano Luminari, Maria Cristina Pirosa, Ferdinando Bonfiglio, Georg Stussi, Wei Wu, Emanuele Zucca, Alden A. Moccia, Renzo Boldorini, Gabriela Forestieri, Franco Cavalli, Alessia Ruffini, Gianluca Gaidano, Luca Mazzucchelli, Valeria Spina, Adalgisa Condoluci, Ricardo Koch, and Anastasios Stathis

Subjects
medicine.medical_specialty, business.operation, business.industry, education, Immunology, Cell Biology, Hematology, Gene mutation, Octapharma, Biochemistry, International Prognostic Index, Continuing medical education, Family medicine, Cohort, Health care, Clinical endpoint, medicine, Progression-free survival, business, health care economics and organizations
Abstract

Introduction Progression of disease within 2 years after starting rituximab-chemotherapy (POD24) has been identified as a convincing adverse prognostic factor for follicular lymphoma (FL), and can serve as a clinical endpoint to identify patients at high risk of early lymphoma-related mortality. However, POD24 is not accessible at diagnosis. Several stratification models adopting baseline variables have been developed for predicting outcomes in FL patients. The Follicular Lymphoma International Prognostic Index (FLIPI) and PRIMA Prognostic-Index (PRIMA-PI) include clinical characteristics, while m7- Follicular Lymphoma International Prognostic Index (m7-FLIPI) and POD24 Prognostic Index (POD24-PI) integrate gene mutations with clinical features. Moreover, the mutation status of specific genes (including TP53, EZH2, TNFRSF14, and BCL2) has been reported to be relevant to early progression. It has been reported that m7-FLIPI and POD24-PI are predictive for POD24. Here we compare the diagnostic accuracy for POD24 of various stratification models and gene mutations in an institutional cohort of FL. Methods Consecutive patients diagnosed as FL grades 1-3a were enrolled from the Oncology Institute of Southern Switzerland (n=75), the University of Eastern Piedmont (n=118), and the Hematology of the AUSL IRCCS of Reggio Emilia (n=59). DNA was extracted from FFPE tissue specimen obtained at diagnosis. We performed CAPP-seq to detect the mutation status of the genes included in m7-FLIPI and POD24 PI (EZH2,ARID1A, MEF2B, EP300, FOXO1, CREBBP, and CARD11), as well as BCL2, TNFRSF14 and TP53. POD24 was the primary endpoint of this research. Sensitivity, specificity, predictive values and balanced accuracy of every stratification model were calculated to estimate the prognostic efficacy. Results With FLIPI score, 34% of patients were classified as low risk, 22% as intermediate risk, and 41% as high risk. With PRIMA-PI, the fractions for low risk, intermediate risk and high risk group were 24%, 21% and 49%, respectively. With m7-FLIPI, 82% of patients were low risk, and 15% high risk. For POD24-PI, 65% of patients were low risk, and 32% high risk. The mutation frequencies of TP53, TNFRSF14, EZH2 and BCL2 were 8%, 28%, 27% and 38%, respectively. We validated the prognostic utility of FLIPI, PRIMA-PI, m7-FLIPI and POD24-PI for progression free survival (PFS) and OS. However, no statistically significant relevance with PFS or OS has been found for TP53, TNFRSF14, EZH2 or BCL2 mutations. POD24 was calculated in the 142 patients who received systemic treatment (immunotherapy or chemoimmunotherapy) within 6 months from diagnosis: 18% of them were POD24-positive. POD24 positivity associated with shorter overall survival (OS) (p=0.0138). After adjusting for multiple comparisons, no high-risk groups identified by TNFRSF14, EZH2 or BCL2 gene mutations, FLIPI, PRIMA-PI, m7-FLIPI or POD24-PI were associated with POD24. In terms of diagnostic performance for POD24, PRIMA-PI showed the highest accuracy (57%), FLIPI had the highest positive predictive value (64%), and m7-FLIPI had the highest negative predictive value (82%). Conclusion The mutation status of specific single genes were not related to POD24, PFS nor OS, indicating that the mutation of single gene may not be sufficient to identify high-risk FL patients. Though retaining their prognostic value, the integration of mutations onto the clinical biomarker-based prognostic scores has a limited discrimination capacity for POD24. Our results prompt the investigation of: i) POD discrimination capacity of prognostic models based on molecular phenotypes (i.e. gene expression) reflecting the tumor-microenvironment milieu; ii) new models based on a combination of biomarkers capturing the most informative clinical, genetic and phenotypic features. Figure 1 Disclosures Moccia: Takeda: Consultancy, Other: Advisory Boards: Roche, Janssen, Takeda; Roche: Consultancy, Other: Advisory Boards: Roche, Janssen, Takeda; Janssen: Consultancy, Other: Advisory Boards: Roche, Janssen, Takeda. Stathis:ADC Therapeutcis: Other, Research Funding; Abbvie: Other: Travel Grant; MEI Pharma: Other, Research Funding; Novartis: Other, Research Funding; Roche: Other, Research Funding; Pfizer: Other, Research Funding; PharmaMar: Other: Travel Grant; Cellestia: Research Funding; Loxo: Honoraria, Other, Research Funding; Member of the steering committee of the trial of this abstract: Other; Bayer: Other, Research Funding; Merck: Other, Research Funding. Gerber:Alnylam: Other: funding for accredited continuing medical education; Axonlab: Other: funding for accredited continuing medical education program ; Bayer: Other: funding for accredited continuing medical education program ; Bristol Myers Squibb: Other: funding for accredited continuing medical education program ; Daiichi-Sankyo: Other: funding for accredited continuing medical education program ; Janssen: Other: funding for accredited continuing medical education program ; Mitsubishi Tanabe Pharma: Other: funding for accredited continuing medical education program ; NovoNordisk: Other: funding for accredited continuing medical education program ; Octapharma: Other; Takeda: Other; Sanofi: Other; SOBI: Other; Thermo Fishe: Other; Axonlab: Other; Pfizer: Other: personal fees ; Sanofi: Other: funding for accredited continuing medical education. Gaidano:Janssen: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Abbvie: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Astrazeneca: Membership on an entity's Board of Directors or advisory committees; Sunesys: Membership on an entity's Board of Directors or advisory committees. Rossi:Gilead: Honoraria, Research Funding; Janssen: Honoraria, Research Funding; Abbvie: Honoraria, Research Funding; AstraZeneca: Honoraria, Research Funding. Zucca:Roche: Membership on an entity's Board of Directors or advisory committees, Other: Travel Grants, Research Funding; Celltrion Healthcare: Membership on an entity's Board of Directors or advisory committees; Kite: Membership on an entity's Board of Directors or advisory committees; Abbvie: Other: Travel Grants; Beigene: Membership on an entity's Board of Directors or advisory committees; Incyte: Membership on an entity's Board of Directors or advisory committees; AstraZeneca: Research Funding; Celgene: Membership on an entity's Board of Directors or advisory committees, Research Funding; Janssen: Membership on an entity's Board of Directors or advisory committees, Research Funding; Merck: Membership on an entity's Board of Directors or advisory committees, Research Funding.

Published
2020
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13. Poster: CLL-358: Adaptation of Chronic Lymphocytic Leukemia to Ibrutinib Is Mediated by Epigenetic Plasticity of Residual Disease and Bypass Signaling via the MAPK Pathway

Author

Lodovico Terzi di Bergamo, Gabriela Forestieri, Jui Wan Loh, Amartya Singh, Valeria Spina, Antonella Zucchetto, Adalgisa Condoluci, Martin Faderl, Ricardo Koch, Alessio Bruscaggin, Katia Pini, Wei Wu, Deborah Piffaretti, Tamara Bittolo, Erika Tissino, Lorenzo De Paoli, Clara Deambrogi, Anna Maria Frustaci, Francesco Autore, Michele Merli, Lydia Scarfò, Silvia Rasi, Jakob Passweg, Riccardo Moia, Claudio Martines, Paolo Ghia, Franco Cavalli, Emanuele Zucca, Bernhard Gerber, Silke Gillessen, Georg Stüssi, Marco Montillo, Francesco Passamonti, Michael Gregor, Luca Laurenti, Alessandra Tedeschi, Gianluca Gaidano, Dimitar Efremov, Valter Gattei, Hossein Khiabanian, and Davide Rossi

Subjects
Cancer Research, Oncology, Hematology
Published
2021
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14. Van Gogh Dylan

Author

Ricardo Koch Kroeff and Ricardo Koch Kroeff

Abstract

Quando Bob Dylan encontra Van Gogh em um momento onírico ou alucinado, recebe um valioso e assustador conselho sobre arte. Esta é a versão totalmente em português do conto publicado no livro Idioma de um só.

Published
2020

15. Idioma de um só

Author

Ricardo Koch Kroeff and Ricardo Koch Kroeff

Abstract

Se você estivesse lá, perguntaria para si mesmo: eu sou real?! Os contos de Idioma de um só namoram as pinturas surrealistas de Salvador Dalí e por isso, com força, certeza, imagens e cores, puxam os sentidos do leitor para dentro do mundo mole dos sonhos. Pianos, bailarinas, Amazônia, tenistas, índios, sexo, Bob Dylan, Van Gogh, drogas: esta obra onírica e sedutora é construída por personagens que, apenas quando necessário, tocam os pés no chão.

Published
2016

17. Análise retrospectiva de casos tratados de trigger points

Author

Wagner, João Carlos Birnfeld, primary, Volkweis, Mauricio Roth, additional, Zaffari, Luciana, additional, Meinke, Gabriela Severo, additional, Brandalise, João Ricardo Koch, additional, Zamboni, Rodrigo Andrighetti, additional, and Lepper, Tatiana Wannmacher, additional

Published
2018
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18. Deng Linlin

Author

Kroeff, Ricardo Koch, Hohlfeldt, Ant?nio Carlos, and 057.024.610-53

Subjects
CONTOS BRASILEIROS, ESCRITA CRIATIVA, LETRAS [LINGUISTICA, LETRAS E ARTES]
Abstract

Esse ? um trabalho para o Mestrado em Escrita Criativa e ? formado por duas partes: um livro de contos (parte um, chamada de Deng Linlin) e ensaios (parte dois, chamada Linlin Deng) sobre essa mesma fic??o. Esses escritos est?o todos em conex?o com o surrealismo e com o lugar onde os sonhos dormem. O realismo est? aqui tamb?m, mas apenas em situa??es onde, se voc? estivesse l?, perguntaria: isso ? um sonho? O primeiro ensaio versa sobre a narrativa, sobre detalhes e t?cnicas espec?ficas do fazer de uma hist?ria. O segundo ensaio ? mais abstrato, e pesquisa o lugar das coincid?ncias no processo criativo, sobre onde elas pertencem e o que querem dizer. O ?ltimo ensaio ? a an?lise do estilo de Bob Dylan na escrita de m?sicas, estilo este usado para emular sua voz em um dos contos. This is a work for the Master in Creative Writting and is formed by two parts: a book with short stories (part one, called Deng Linlin) and essays (part two, called Linlin Deng) about that same fiction. This writtings are all in connection with surrealism and with the place where dreams fall asleep. Realism is here too, but only in situations where, if you were there, would question yourself: is this a dream? The first essay is about narrative, about details and specific techniques of story telling. The second essay is more abstractive, and searches the place of coincidences in the creative process, where do they belong and what do they mean. The last essay is an analisys of Bob Dylan?s style in song writting. This analysis was used for emulating his voice in one of the short stories.

Published
2015

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